This application requests support to continue our exploration of beta-peptide structure and biologic function. We build herein on two of the most exciting and impacting discoveries of the first funding cycle: (1) that carefully designed beta-peptides effectively mimic - helices and function as protein interaction inhibitors, with properties that are easily improved by combinatorial methods; and (2) that beta-peptides can be engineered to traverse the plasma membrane and retain biologic function in the cytosol, without the addition of a large octa-arginine tag, facilitating their application to intracellular targets. Thus, the Specific Aims of this application are to first (Aim 1) move away from proof-of- principle targets, and design beta-peptide ligands for two well-validated drug targets that could benefit from the unique combination of properties embodied by a beta-peptide: the GLP-1 receptor (GLP-1R), a target of the antidiabetes drug Byetta, and the ErbB2 receptor, a target of the mAb Herceptin. We also describe beta-peptides that either inhibit or activate CXCR4 and CCR5 chemokine receptors from within the plasma membrane. In Aim 2, we described experiments to systematically optimize and exploit cell- permeable beta-peptides as a first step toward broadening their applicability to cytosolic targets. The fact that beta-peptides are immune to proteolytic degradation makes them uniquely capable of reporting on the myriad pathways by which peptides achieve uptake and traffic within the cell once they do.